Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Eye and Systemic Disease_Wright, Spiegel, Thompson_2006

and their first-degree relatives should be screened for VHL.75 The younger the age of presentation in a patient with a retinal hemangioblastoma, the greater the likelihood of VHL. Multiple retinal hemangioblastomas are diagnostic of VHL. Two clinical types of hemangioblastomas of retinal and optic head are recognized: an endophytic and the less common exophytic tumor.36 The endophytic hemangioma projects into the vitreous. Early lesions are minute reddish nodules with afferent and efferent vessels. Peripheral tumors are recognized by a smooth, elevated, round contour and are white to orange or reddish in color. More advanced large peripheral tumors are fed by a markedly dilated tortuous arteriole, with a dilated, efferent venule draining the lesion. Indirect ophthalmoscopy fluorescein angiography may be necessary to identify early small hemangiomas that resemble capillary dilations. Patients remain asymptomatic until visual loss occurs, usually in the second to third decade.

Visual loss can be a result from exudative or traction retinal detachment, macular edema or holes, epiretinal membranes, vitreous hemorrhages, neovascular glaucoma, uveitis, or postpapilledema optic atrophy. Exophytic tumors arise from the outer retina and occur most commonly in the peripapillary region. Their blood supply is from the retinal and posterior ciliary circulation.36 On fluorescein angiography there is early filling of the angiomas during the arteriole phase. Twin vessels, the closely paired feeding arteriole and draining venule of larger, peripheral tumors, are clearly depicted with angiography. Hemangioblastomas may involve the optic disc, or the peripapillary retina, or occur within the optic nerve itself. Hemangioblastomas of the optic nerve causing progressive and compressive optic neuropathy are rare and may be confused with optic nerve tumors. Discordance between the retinal appearance and signs of optic nerve dysfunction may suggest the diagnosis. Surgical excision of the hemangioblastoma to preserve vision may be possible because the tumor does not infiltrate the optic nerve.

Clinical Assessment

The features of VHL disease, which can cause significant morbidity and mortality, are all potentially treatable if diagnosed early. This realization has led to development of screening protocols for the follow-up of affected individuals and at-risk relatives. Screening guidelines for affected individuals and at-risk family members are given in Table 6-8.75

syndrome. Some patients require emergent treatment for lifethreatening CNS disease. The benign vascular tumors can hemorrhage, causing obstructive hydrocephalus, and are difficult to remove surgically because of their vascularity. Early detection permits treatment, which lessens the risk of spinal cord compression and sudden death in VHL patients. However, surgical excision is difficult because of tumor vascularity, and recurrence is likely.

Clear cell carcinoma of the kidney is the presenting illness in 10% of patients with VHL disease. The cumulative risk of developing renal cell carcinoma is more than 70% by age 60 years and it is the leading cause of death in VHL disease. Ultrasonographic (or even MRI) screening of asymptomatic patients is therefore advised. Pheochromocytoma is another visceral manifestation of VHL disease that is found in 7% to 18% of all VHL patients.71 Approximately 19% of newly diagnosed pheochromocytomas are caused by VHL disease. As with other tumors, VHL-associated pheochromocytomas occur at an earlier age than nonfamilial cases and are multifocal in 55% of cases. Cysts of the kidneys, pancreas, and epididymis are common and do not appear to undergo malignant transformation. Papillary adenocarcinoma of the endolymphatic sac with bony erosion and hearing loss is believed to occur in 8% of patients. Polycythemia caused by tumor erythropoietin production occurrs in 5% to 20% of cases and is usually related to cerebellar hemangioblastomas and renal cell carcinomas.45 Cutaneous lesions are rare in VHL disease.

Clinical Assessment

Guidelines for screening for von Hippel–Lindau disease in affected patients and at-risk relatives are given in Table 6-8.

Inheritance

von Hippel–Lindau disease is an autosomal dominantly inherited condition.

Natural History

The mean age at presentation of the symptomatic cases in the Cambridge series was 27 12.6 years.69 As in other neurocutaneous syndromes, the national history depends on which lesions develop. In unscreened populations, the disease is associated

and pancreatic tumors. The outcome of treatment, usually surgical, depends on the stage at which these vascular tumors become symptomatic, as well as their location.

Treatment

Surgical removal of tumors, when possible, is the primary treatment available. (See Natural History section for further discussion.)

ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurological and immunogical symptoms, radiosensitivity, and cancer predisposition. This disease was initially described by Louis-Bar in 1941.65

Incidence

The incidence of A-T is estimated at 1 per 40,000 live births. The carrier frequency is approximately 1%.37

Etiology

A-T is a very pleiotropic syndrome that stems from the defective functioning of a mutated ATM gene. ATM belongs to a large molecular weight family of protein kinases. Delayed or reduced expression of p53 in radiation-damaged A-T cells suggests that ATM interacts with proteins upstream of p53 sensing doublestrand break DNA damage. Seventy percent of ATM mutations result in a short truncated protein. These mutations are found over the entire gene.37

Ophthalmologic Features

This disorder presents in early childhood with the onset of ataxia at the time the child is learning to walk. Conjunctival telangiectasia develops between the ages of 4 and 7 (Fig. 6-7). The telangiectasias are a hallmark of A-T. The ocular telangiectasia consists of dilated and corkscrew, bulbar conjunctival vessels located in the interpalpebral zone of both eyes. Ocular motor apraxia with head thrusts and the inability to generate

saccades and loss of optokinetic responses develop at a later age.37

Clinical Assessment

Every A-T homozygote has a small embryonic-like thymus; 60% to 80% of A-T of the homozygotes manifest an IgA, IgE, or IgG2 deficiency. Serum alpha-fetoprotein (AFP) levels are elevated in 95% of A-T patients. AFP levels should be determined after 2 years of age. The gene for A-T is located at 11q23.1. Karyotyping, if successful, reveals translocations involving chromosomes 14q11, 14q32, 7q35, and 7p14. MRI of the cerebellum will usually show marked atrophy in children over 4 years of age (Fig. 6-7B]. Newer techniques for imaging the cerebellum are also being evaluated such as functional MRI. DNA testing, now that the gene was positionally cloned from 11q23.1, can be used for prenatal testing.37

Systemic Associations

Progressive neurological dysfunction includes truncal ataxia, choreoathetosis, dystonia, and myoclonus, slurring of speech, and drooling. Oculocutaneous telangiectasias, usually present by 6 years of age, affect the malar region, nose, and ears. Premature aging occurs, and endocrine dysfunction causes hyperglycemia, hypogonadism, and growth retardation. Frequent, recurrent sinopulmonary and skin infections are caused by serum and immunodeficiencies. A-T patients have susceptibility to cancer, usually leukemia or lymphoma. Their hypersensitivity to ionizing radiation calls for modified dosing of radiation therapy for cancer.37

Natural History

Growth deficiency may be prenatal in onset, but more commonly becomes evident in later infancy or in childhood. Ataxia usually develops during infancy and eventually is accompanied by choreoathetosis, slurring of speech, drooling, ocular motor apraxia, stooped posture, presence of a dull, sad facies, and, occasionally, seizures. Ataxia often becomes so severe that ambulation is no longer possible in later childhood. Death is usually a consequence of lung infections, neurological deficit, or malignancy.37

Treatment

No effective therapy exists for halting the progression of the ataxia. Clinical trials are under way to test the efficacy of myoinositol, N-acetylcystine, and L-dopa on general symptoms. To date, preliminary data have been disappointing. Vitamin E, alpha-lipoic acid, and coenzme Q10 may also slow the deterioration. Folic acid may help to minimize chromosomal fragility and the formation of double-strand DNA breaks. Pulmonary or sinus infections may be treated conventionally because the normal spectrum of microbes is present. If possible, neurotoxic chemotherapeutic agents should be avoided. Patients with bronchiectasis are best treated in a similar fashion to patients with cystic fibrosis. In older patients, pulmonary infections are the major cause of failing health and death. In addition to appropriate antibiotics, intravenous gamma globulin every 3 to 4 weeks may reduce the frequency of infections.37 Of paramount importance is an aggressive and engaging physical exercise program aimed at enhancing lung function, preventing contractures, and avoiding positional kyphoscoliosis.

Various agents can partially relieve some of the neurological symptoms, such as ataxia, drooling, and tremors. Buspirone is active in some types of cerebellar ataxia. Amantadine improves balance and coordination and minimizes drooling.37 When radiation therapy is planned for treating a malignancy the dose should be reduced by approximately 30%. Some chemotherapeutic agents, especially alkylating agents, should also be given in reduced doses.37

Prognosis

Most A-T patients in the United States now live well beyond 20 years of age. Unfortunately, this major improvement from just a few years ago has not been universal. The improved survival in the United States may be related to better nutrition, better diagnostics, better treatment of pulmonary infections and malignancies, and more aggressive physical therapy. The application of an effective treatment given before neurological decline would represent a great advance.

STURGE–WEBER SYNDROME

Sturge–Weber syndrome (SWS) is a neurocutaneous disorder characterized by cutaneous facial angiomas, leptomeningeal angiomas, and seizures and other neurological complications, including mental retardation and glaucoma.

Incidence

The SWS occurs sporadically. Facial angiomas (port-wine stains, nevus flammeus) occur in 3 per 1000 births; however, only 5% of patients demonstrate the full features of SWS.47

Etiology

There are no reports of familial occurrence of Sturge–Weber syndrome. The condition may be more prevalent in Caucasians than in other races. There has been one report of a chromosomal abnormality at fragile site 10q24 in a young boy with this syndrome106 and a supernumerary bisatellited chromosome. The family had several unaffected members.28

It is hypothesized that the primary lesion in Sturge–Weber is a maldevelopment of vasculature at 4 to 8 weeks gestational age. This flaw leads to fibrosis, hyaline degeneration, dilation and calcification of the vascular wall with venous wall stasis, recurrent thrombotic events, transient ischemic attacks, and gradual neurological deterioration. Another possible embryologic basis for this syndrome is a defective migration and differentiation of the promesencephalic neural crest, leading to abnormal proliferation of blood vessels and goniodysgenesis.91

Ophthalmologic Features

The ocular manifestations of SWS are listed in Table 6-10. The area of the ophthalmic division of the trigeminal nerve is often affected with nevus flammeus, including the upper eyelid and the conjunctiva (Fig. 6-8). Up to 30% of SWS patients have bilateral facial lesions (Fig. 6-9); 40% of patients with SWS may have choroidal hemangioma, and 50% of all choroidal hemangiomas occur in SWS patients. Choroidal hemangiomas may be discrete, appearing as yellowish, elevated, circular areas, which disappear or decrease in visibility with scleral depression. The diffuse type occurs more commonly in SWS patients and the age on onset of